The present invention relates generally to a series of novel small molecules, their synthesis and their use in the treatment of inflammatory disease.
Research spanning the last decade has helped to elucidate the molecular events attending cell-cell interactions in the body, especially those events involved in the movement and activation of cells in the immune system. See generally, Springer, T. Nature, 1990, 346, 425-434. Cell surface proteins, and especially the Cellular Adhesion Molecules (xe2x80x9cCAMsxe2x80x9d) and xe2x80x9cLeukointegrinsxe2x80x9d including LFA-1, MAC-1 and gp 150.95 (referred to in WHO nomenclature as CD18/CD11a, CD18/CD11b, and CD18/CD11c, respectively) have correspondingly been the subject of pharmaceutical research and development having as its goal the intervention in the processes of leukocyte extravasation to sites of injury and leukocyte movement to distinct targets. For example, it is presently believed that prior to the leukocyte extravasation, which is a mandatory component of the inflammatory response, activation of integrins constitutively expressed on leukocytes occurs and is followed by a tight ligand/receptor interaction between integrins (e.g., LFA-1) and one or several distinct intercellular adhesion molecules (ICAMs) designated ICAM-1, ICAM-2, ICAM-3 or ICAM-4 which are expressed on blood vessel endothelial cell surfaces and on other leukocytes. The interaction of the CAMs with the Leukointegrins is a vital step in the normal functioning of the immune system. Immune processes such as antigen presentation, T-cell mediated cytotoxicity and leukocyte extravasation all require cellular adhesion mediated by ICAMs interacting with the Leukointegrins. See generally Kishimoto, T. K.; Rothlein; R. R. Adv. Pharmacol. 1994, 25, 117-138 and Diamond, M.; Springer, T. Current Biology, 1994, 4, 506-532.
A group of individuals has been identified which lack the appropriate expression of Leukointegrins, a condition termed xe2x80x9cLeukocyte Adhesion Deficiencyxe2x80x9d (Anderson, D. C.; et al., Fed. Proc. 1985, 44, 2671-2677 and Anderson, D. C.; et al., J. Infect. Dis. 1985, 152, 668-689). These individuals are unable to mount a normal inflammatory and/or immune response(s) due to an inability of their cells to adhere to cellular substrates. These data show that immune reactions are mitigated when lymphocytes are unable to adhere in a normal fashion due to the lack of functional adhesion molecules of the CD18 family. By virtue of the fact that LAD patients who lack CD18 cannot mount an inflammatory response, it is believed that antagonism of CD18, CD11/ICAM interactions will also inhibit an inflammatory response.
It has been demonstrated that the antagonism of the interaction between the CAMs and the Leukointegrins can be realized by agents directed against either component, Specifically, blocking of the CAMs, such as for example ICAM-1, or the Leukointegrins, such as for example LFA-1, by antibodies directed against either or both of these molecules effectively inhibits inflammatory responses. In vitro models of inflammation and immune response inhibited by antibodies to CAMs or Leukointegrins include antigen or mitogen-induced lymphocyte proliferation, homotypic aggregation of lymphocytes, T-cell mediated cytolysis and antigen-specific induced tolerance. The relevance of the in vitro studies are supported by in vivo studies with antibodies directed against ICAM-1 or LFA-1. For example, antibodies directed against LFA-1 can prevent thyroid graft rejection and prolong heart allograft survival in mice (Gorski, A.; Immunology Today, 1994, 15, 251-255). Of greater significance, antibodies directed against ICAM-1 have shown efficacy in vivo as anti-inflammatory agents in human diseases such as renal allograft rejection and rheumatoid arthritis (Rothlein, R. R.; Scharschmidt, L., in: Adhesion Molecules; Wegner, C. D., Ed.; 1994, 1-38, Cosimi, C. B.; et al., J. Immunol. 1990, 144, 4604-4612 and Kavanaugh, A.; et al., Arthritis Rheum. 1994, 37, 992-1004) and antibodies directed against LFA-1 have demonstrated immunosuppressive effects in bone marrow transplantation and in the prevention of early rejection of renal allografts (Fischer, A.; et al., Lancet, 1989, 2, 1058-1060 and Le Mauff, B.; et al., Transplantation, 1991, 52, 291-295).
It has also been demonstrated that a recombinant soluble form of ICAM-1 can act as an inhibitor of the ICAM-1 interaction with LFA-1. Soluble ICAM-1 acts as a direct antagonist of CD18, CD11/ICAM-1 interactions on cells and shows inhibitory activity in in vitro models of immune response such as the human mixed lymphocyte response, cytotoxic T cell responses and T cell proliferation from diabetic patients in response to islet cells (Becker, J. C.; et al., J. Immunol. 1993, 151, 7224 and Roep, B. O.; et al., Lancet, 1994, 343, 1590).
Thus, the prior art has demonstrated that large protein molecules which antagonize the binding of the CAMs to the Leukointegrins have therapeutic potential in mitigating inflammatory and immunological responses often associated with the pathogenesis of many autoimmune or inflammatory diseases. However proteins have significant deficiencies as therapeutic agents, including the inability to be delivered orally and potential immunoreactivity which limits the utility of theses molecules for chronic administration. Furthermore, protein-baged therapeutics are generally expensive to produce.
Several small molecules have been described in the literature which affect the interaction of CAMs and Leukointegrins. A natural product isolated from the root of Trichilia rubra was found to be inhibitory in an in vitro cell binding assay (Musza, L. L.; et al., Tetrahedron, 1994, 50, 11369-11378). One series of molecules (Boschelli, D. H.; et al., J. Med. Chem. 1994, 37, 717 and Boschelli, D. H.; et al., J. Med. Chem. 1995, 38, 4597-4614) was found to be orally active in a reverse passive Arthus reaction, an induced model of inflammation that is characterized by neutrophil accumulation (Chang, Y. H.; et al., Eur. J. Pharmacol. 1992, 69, 155-164). Another series of molecules was also found to be orally active in a delayed type hypersensitivity reaction in rats (Sanfilippo, P. J.; et al., J. Med. Chem. 1995, 38, 1057-1059). All of these molecules appear to act nonspecifically, either by inhibiting the transcription of ICAM-1 along with other proteins or act intracellularly to inhibit the activation of the Leukointegrins by an unknown mechanism. None of the molecules directly antagonize the interaction of the CAMs with the Leukointegrins. Due to lack of potency, lack of selectivity and lack of a specific mechanism of action, the described small molecules are not likely to be satisfactory for therapeutic use.
It follows that small molecules having the similar ability as large protein molecules to directly and selectively antagonize the binding of the CAMs to the Leukointegrins would make preferable therapeutic agents. WO9839303 discloses a class of small molecule inhibitors of the interaction of LFA-1 and ICAM-1. WO9911258 discloses that the fungal metabolite mevinolin and derivatives bind to LFA-1 and disrupt the interaction of LFA-1 and ICAM-1.
A first aspect of the invention comprises a method for treating or preventing inflammatory and immune cell-mediated diseases by the administration of certain novel small molecules. These compounds act by inhibiting the interaction of cellular adhesion molecules, specifically by antagonizing the binding of human intercellular adhesion molecules (including ICAM-1, ICAM-2 and ICAM-3) to the Leukointegrins (especially CD18/CD11a). A second aspect of the invention comprises novel small molecules having the above-noted therapeutic activities. A third aspect of the invention comprises methods for making these novel compounds. A final aspect of the invention comprises pharmaceutical compositions comprising the above-mentioned compounds suitable for the prevention or treatment of inflammatory and immune cell-mediated conditions.
The invention comprises compounds of the formula I 
wherein:
is 0 or 1,
is 0 or 1, and
m+n is equal to either 1 or 2;
Y is an oxygen or sulfur atom;
Z is an oxygen or sulfur atom;
R1 is:
(A) a hydrogen atom, or
(B) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms wherein said alkyl or cycloalkyl group may optionally be substituted with:
(i) a group of the formula xe2x80x94OR10, wherein R10 is an alkyl or acyl group of 1 to 2 carbon atoms,
(ii) a group of the formula xe2x80x94NR11R12, wherein R11 and R12 are each, independently, alkyl of 1 to 2 carbon atoms, or acyl of 1 to 2 carbon atoms, or
(C) a group of the formula xe2x80x94OR13, wherein R13 is a an alkyl or acyl group of 1 to 2 carbon atoms;
R2 is:
aryl selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-midazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzor[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl,
xe2x80x83wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) R14, which is aryl selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl,
xe2x80x83wherein one or more of the hydrogen atoms of said R14 aryl group may be optionally and independently replaced with:
(a) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(b) a group of the formula xe2x80x94COOR15, wherein R15 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(c) a group of the formula xe2x80x94NR16R17, wherein R16 and R17 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R16 and R17 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(d) a group of the formula xe2x80x94CONR18R19, wherein R18 and R19 are each independently a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R18 and R19 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(e) a group of the formula xe2x80x94OR20, wherein R20 is a hydrogen atom, or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(f) a group of the formula xe2x80x94SR21, wherein R21 is a hydrogen atom, or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(g) cyano,
(h) nitro,
(i) halogen,
(ii) methyl, which may be mono- or polysubstituted with fluorine atoms,
(iii) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(iv) a group of the formula xe2x80x94COOR22, wherein R22 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(v) a group of the formula xe2x80x94NR23R24, wherein R23 and R24 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R23 and R24 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vi) a group of the formula xe2x80x94CONR25R26, wherein R25 and R26 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R25 and R26 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) a group of the formula xe2x80x94COR27, wherein R27 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, or cycloalkyl of 3 to 5 carbon atoms,
(viii) a group of the formula xe2x80x94OR28, wherein R28 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(ix) a group of the formula xe2x80x94SR29, wherein R29 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(x) cyano,
(xi) nitro, or
(xii) halogen,
R3 is:
(A) a hydrogen atom, or
(B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms wherein said alkyl or cycloalkyl group may optionally be substituted with:
(i) a group of the formula xe2x80x94OR30, wherein R30 is a hydrogen atom, or an alkyl or acyl group of 1 to 6 carbon atoms,
(ii) a group of the formula xe2x80x94NR31R32, wherein R31 and R32 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, or acyl of 1 to 6 carbon atoms, or
(C) a group of the formula xe2x80x94OR33, wherein R33 is a hydrogen atom, or an alkyl or acyl group of 1 to 6 carbon atoms;
R4 is Cl or trifluoromethyl;
X is xe2x95x90Nxe2x80x94 or xe2x95x90CR5xe2x80x94,
wherein R5 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl;
R6 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl, cyano, nitro or trifluoromethyl, with the condition that when X is N or xe2x95x90CHxe2x80x94, R6 is chlorine or trifluoromethyl,
R7, R8 and R9 are each, independently:
(A) a hydrogen atom,
(B) an oxo group, or
(C) R34, OR34, NHR34, COR34, CONHR34, COOR34, SO2R34, or SR34
xe2x80x83wherein R34 is defined as:
(i) A hydrogen atom,
(ii) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with:
(a) halogen,
(b) oxo,
(c) aryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl,
xe2x80x83wherein one or more hydrogen atoms of said aryl group may be optionally and independently replaced with:
(1) alkyl of 1 to 3 carbon atoms,
(2) xe2x80x94COOH,
(3) xe2x80x94SO2OH,
(4) xe2x80x94PO(OH)2,
(5) a group of the formula xe2x80x94COOR35, wherein R35 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(6) a group of the formula xe2x80x94NR36R37, wherein R36 and R37 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R36 and R37 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(7) a group of the formula xe2x80x94CONR38R39, wherein R38 and R39 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R38 and R39 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(8) a group of the formula xe2x80x94OR40, wherein R40 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(9) a group of the formula xe2x80x94SR41, wherein R41 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(10) cyano,or
(11) an amidino group of the formula 
xe2x80x83wherein R42, R43 and R44 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of R42, R43 and R44 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(d) a group of the formula xe2x80x94COOR45, wherein R45 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,
(e) cyano,
(f) a group of the formula xe2x80x94CONR46R47, wherein R46 and R47 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R46 and R47 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(g) a group of the formula xe2x80x94OR48, wherein R48 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(h) a group of the formula xe2x80x94SR49, wherein R49 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(i) a group of the formula xe2x80x94NR50R51, wherein R50 and R51 are each, independently,
(1) a hydrogen atom,
(2) alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms,
(3) a group of the formula xe2x80x94(CH2)tCOOH, wherein t is O, 1 or 2, or
(4) a group of the formula xe2x80x94(CH2)uCOOR52, wherein u is 0, 1 or 2, wherein R52 is straight or branched alkyl of 1 to 6 carbon atoms,
xe2x80x83or wherein R50 and R51 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or
(j) a quaternary group of the formula 
xe2x80x83wherein R53, R54 and R55 are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Q- is a chlorine, bromine or iodine counterion,
(iii) a branched or unbranched carboxylic acid group of 2 to 6 carbon atoms,
(iv) a branched or unbranched phosphonic acid group of 2 to 6 carbon atoms,
(v) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,
(vi) an amidino group of the formula 
wherein r is 2, 3, 4, 5 or 6, and R56, R57 and R58 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R56, R57 and R58 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(vii) a guanidino group of the formula 
wherein s is 2, 3, 4, 5 or 6, and
R59, R60, R61 and R62 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R59, R60, R61 and R62 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(viii) aryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl,
xe2x80x83wherein one or more hydrogen atoms of said aryl group may be optionally and independently replaced with:
(a) alkyl of 1 to 3 carbon atoms,
(b) xe2x80x94COOH,
(c) xe2x80x94SO2OH,
(d) xe2x80x94PO(OH)2,
(e) a group of the formula xe2x80x94COOR63, wherein R63 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(f) a group of the formula xe2x80x94NR64R65, wherein R64 and R65 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R64 and R65 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(g) a group of the formula xe2x80x94CONR66R67, wherein R66 and R67 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R66 and R67 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(h) a group of the formula xe2x80x94OR68, wherein R68 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(i) a group of the formula xe2x80x94SR69, wherein R69 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(j) cyano,
(k) or, an amidino group of the formula 
xe2x80x83wherein R70, R71 and R72 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R70, R71 and R72 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring;
with the proviso that R1 and R2 are in the trans configuration.
and pharmaceutically acceptable salts thereof.
Preferred are compounds of the formula I, wherein:
m is 0 or 1,
n is 0 or 1, and
m+n is equal to either 1 or 2;
Y is an oxygen or sulfur atom;
Z is an oxygen or sulfur atom;
R1 is:
(A) a hydrogen atom, or
(B) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms wherein said alkyl or cycloalkyl group may optionally be substituted with:
(i) a group of the formula xe2x80x94OR10, wherein R10 is an alkyl or acyl group of 1 to 2 carbon atoms,
(ii) a group of the formula xe2x80x94NR11R12, wherein R11 and R12 are each, independently, alkyl of 1 to 2 carbon atoms, or acyl of 1 to 2 carbon atoms, or
(C) a group of the formula xe2x80x94OR13, wherein R13 is a an alkyl or acyl group of 1 to 2 carbon atoms;
R2 is:
aryl selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl,
xe2x80x83wherein one or more of the hydrogen atoms of said aryl group may be optionally and independently replaced with:
(i) R14, which is aryl selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, 3-, 6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or 6-benztiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl,
xe2x80x83wherein one or more of the hydrogen atoms of said R14 aryl group may be optionally and independently replaced with:
(a) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(b) a group of the formula xe2x80x94COOR15, wherein R15 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(c) a group of the formula xe2x80x94NR16R17, wherein R16 and R17 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R16 and R17 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(d) a group of the formula xe2x80x94CONR18R19, wherein R18 and R19 are each independently a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R18 and R19 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(e) a group of the formula xe2x80x94OR20, wherein R20 is a hydrogen atom, or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(f) a group of the formula xe2x80x94SR21, wherein R21 is a hydrogen atom, or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(g) cyano,
(h) nitro,
(i) halogen,
(ii) methyl, which may be mono- or polysubstituted with fluorine atoms,
(iii) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(iv) a group of the formula xe2x80x94COOR22, wherein R22 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(v) a group of the formula xe2x80x94NR23R24, wherein R23 and R24 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R23 and R24 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vi) a group of the formula xe2x80x94CONR25R26, wherein R25 and R26 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R25 and R26 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) a group of the formula xe2x80x94COR27, wherein R27 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, or cycloalkyl of 3 to 5 carbon atoms,
(viii) a group of the formula xe2x80x94OR28, wherein R28 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(ix) a group of the formula xe2x80x94SR29, wherein R29 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(x) cyano,
(xi) nitro, or
(xii) halogen,
R3 is:
(A) a hydrogen atom,
(B) methyl, or
(C) a group of the formula xe2x80x94OR33, wherein R33 is a hydrogen atom methyl;
R4 is Cl or trifluoromethyl;
X is xe2x95x90Nxe2x80x94 or xe2x95x90xe2x80x94OR5xe2x80x94,
xe2x80x83wherein R5 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl;
R6 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl, cyano, nitro or trifluoromethyl, with the condition that when X is N or xe2x95x90CHxe2x80x94, R6 is chlorine or trifluoromethyl;
R7, R8 and R9 are each, independently:
(A) a hydrogen atom,
(B) an oxo group, or
(C) R34, OR34, NHR34, COR34, CONHR34, COOR34, SO2R34, or SR34 
xe2x80x83wherein R34 is defined as:
(i) a hydrogen atom,
(ii) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with:
(a) oxo,
(b) phenyl,
xe2x80x83wherein one or more hydrogen atoms of said phenyl group may be optionally and independently replaced with:
(1) alkyl of 1 to 3 carbon atoms,
(2) xe2x80x94COOH,
(3) xe2x80x94SO2OH,
(4) xe2x80x94PO(OH)2,
(5) a group of the formula xe2x80x94COOR35, wherein R35 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(6) a group of the formula xe2x80x94NR36R37, wherein R36 and R37 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R36 and R37 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(7) a group of the formula xe2x80x94CONR38R39, wherein R38 and R39 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R38 and R39 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(8) a group of the formula xe2x80x94OR40, wherein R40 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(9) a group of the formula xe2x80x94SR41, wherein R41 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(10) cyano,or
(11) an amidino group of the formula 
xe2x80x83wherein R42, R43 and R44 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of R42, R43 and R44 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(c) a group of the formula xe2x80x94COOR45, wherein R45 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,
(d) cyano,
(e) a group of the formula xe2x80x94CONR46R47, wherein R46 and R47 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloakyl of 3 to 6 carbon atoms, or wherein R46 and R47 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(f) a group of the formula xe2x80x94OR48, wherein R48 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(g) a group of the formula xe2x80x94SR49, wherein R49 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(h) a group of the formula xe2x80x94NR50R51, wherein R50 and R51 are each, independently,
(1) a hydrogen atom,
(2) alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms,
(3) a group of the formula xe2x80x94CH2)tCOOH, wherein t is 0, 1or 2, or
(4) a group of the formula xe2x80x94(CH2)uCOOR52, wherein u is 0, 1 or 2, wherein R52 is straight or branched alkyl of 1 to 6 carbon atoms,
xe2x80x83or wherein R50 and R51 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or
(i) a quaternary group of the formula 
xe2x80x83wherein R53, R54 and R55 are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Qxe2x88x92 is a chlorine, bromine or iodine counterion,
(iii) a branched or unbranched carboxylic acid group of 2 to 6 carbon atoms,
(iv) a branched or unbranched phosphonic acid group of 2 to 6 carbon atoms,
(v) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,
(vi) an amidino group of the formula 
xe2x80x83wherein r is 2, 3, 4, 5 or 6, and
R56, R57 and R58 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R56, R57 and R58 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(vii) a guanidino group of the formula 
xe2x80x83wherein s is 2, 3, 4, 5 or 6, and
xe2x80x83R59, R60, R61 and R62 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R59, R60, R61 and R62 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(viii) phenyl,
xe2x80x83wherein one or more hydrogen atoms of said phenyl group may be optionally and independently replaced with:
(a) alkyl of 1 to 3 carbon atoms,
(b) xe2x80x94COOH,
(c) xe2x80x94SO2OH,
(d) xe2x80x94PO(OH)2,
(e) a group of the formula xe2x80x94COOR63, wherein R63 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(f) a group of the formula xe2x80x94NR64R65, wherein R64 and R65 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R64 and R65 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(g) a group of the formula xe2x80x94CONR66R67, wherein R66 and R67 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R66 and R67 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(h) a group of the formula xe2x80x94OR68, wherein R68 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(i) a group of the formula xe2x80x94SR69, wherein R69 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(j) cyano,
(k) or, an amidino group of the formula 
xe2x80x83wherein R70, R71 and R72 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R70, R71 and R72 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring;
with the proviso that R1 and R2 are in the trans configuration;
and pharmaceutically acceptable salts thereof.
More preferred are compounds of the formula I, wherein:
m is 0 or 1,
n is 0 or 1, and
m+n is equal to either 1 or 2;
Y is an oxygen atom;
Z is an oxygen atom;
R1 is:
(A) a hydrogen atom,
(B) methyl, or
(C) a group of the formula xe2x80x94OR13, wherein R13 is a an alkyl or acyl group of 1 to 2 carbon atoms;
R2 is:
xe2x80x83phenyl,
xe2x80x83wherein one or more of the hydrogen atoms of said phenyl group may be optionally and independently replaced with:
(i) R14, which is aryl selected from the class consisting of phenyl, 3-pyridyl, or 5-pyrimidinyl,
xe2x80x83wherein one or more of the hydrogen atoms of said R14 aryl group may be optionally and independently replaced with:
(a) methyl,
(b) cyano,
(c) nitro, or
(d) halogen,
(ii) methyl, which may be mono- or polysubstituted with fluorine atoms,
(iii) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with halogen or oxo,
(iv) a group of the formula xe2x80x94COOR22, wherein R22 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(v) a group of the formula xe2x80x94CONR25R26, wherein R25 and R26 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R25 and R26 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vi) a group of the formula xe2x80x94COR27, wherein R27 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, or cycloalkyl of 3 to 5 carbon atoms,
(vii) a group of the formula xe2x80x94OR28, wherein R28 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(viii) a group of the formula xe2x80x94SR29, wherein R29 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(ix) cyano,
(x) nitro, or
(xi) halogen,
R3 is:
(A) a hydrogen atom,
(B) methyl, or
(C) a group of the formula xe2x80x94OR33, wherein R33 is a hydrogen atom methyl;
R4 is Cl or trifluoromethyl;
X is xe2x95x90Nxe2x80x94 or xe2x95x90xe2x80x94OR5xe2x80x94,
xe2x80x83wherein R5 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl;
R6 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl, cyano, nitro or trifluoromethyl, with the condition that when X is N or xe2x95x90CHxe2x80x94, R6 is chlorine or trifluoromethyl;
R7, R8 and R9 are each, independently:
(A) a hydrogen atom,
(B) an oxo group, or
(C) R34, OR34, NHR34, COR34, CONHR34, COOR34, SO2R34, or SR34 
xe2x80x83wherein R34 is defined as:
(i) a hydrogen atom,
(ii) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with:
(a) oxo,
(b) phenyl,
xe2x80x83wherein one or more hydrogen atoms of said phenyl group may be optionally and independently replaced with:
(1) alkyl of 1 to 3 carbon atoms,
(2) xe2x80x94COOH,
(3) xe2x80x94SO2OH,
(4) xe2x80x94PO(OH)2,
(5) a group of the formula xe2x80x94COOR35, wherein R35 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(6) a group of the formula xe2x80x94NR36R37, wherein R36 and R37 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R36 and R37 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(7) a group of the formula xe2x80x94CONR38R39, wherein R38 and R39 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R38 and R39 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(8) a group of the formula xe2x80x94OR40, wherein R40 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(9) a group of the formula xe2x80x94SR41, wherein R41 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(10) cyano, or
(11) an amidino group of the formula 
xe2x80x83wherein R42, R43 and R44 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of R42, R43 and R44 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(c) a group of the formula xe2x80x94COOR45, wherein R45 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,
(d) cyano,
(e) a group of the formula xe2x80x94CONR46R47, wherein R46 and R47 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R46 and R47 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(f) a group of the formula xe2x80x94OR48, wherein R48 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(g) a group of the formula xe2x80x94SR49, wherein R49 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(h) a group of the formula xe2x80x94NR50R51, wherein R50 and R51 are each, independently,
(1) a hydrogen atom,
(2) alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms,
(3) a group of the formula xe2x80x94CH2)tCOOH, wherein t is O, 1 or 2, or
(4) a group of the formula xe2x80x94(CH2)uCOOR52, wherein u is 0, 1 or 2, wherein R52 is straight or branched alkyl of 1 to 6 carbon atoms,
xe2x80x83or wherein R50 and R51 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or
(i) a quaternary group of the formula 
xe2x80x83wherein R53, R54 and R55 are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Qxe2x88x92 is a chlorine, bromine or iodine counterion,
(iii) a branched or unbranched carboxylic acid group of 2 to 6 carbon atoms,
(iv) a branched or unbranched phosphonic acid group of 2 to 6 carbon atoms,
(v) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,
(vi) an amidino group of the formula 
xe2x80x83wherein r is 2, 3, 4, 5 or 6, and R56, R57 and R58 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R56, R57 and R58 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(vii) a guanidino group of the formula 
xe2x80x83wherein s is 2, 3, 4, 5 or 6, and
xe2x80x83R59, R60, R61 and R62 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R59, R60, R61 and R62 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(viii) phenyl,
xe2x80x83wherein one or more hydrogen atoms of said phenyl group may be optionally and independently replaced with:
(a) alkyl of 1 to 3 carbon atoms,
(b) xe2x80x94COOH,
(c) xe2x80x94SO2OH,
(d) xe2x80x94PO(OH)2,
(e) a group of the formula xe2x80x94COOR63, wherein R63 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(f) a group of the formula xe2x80x94NR64R65, wherein R64 and R65 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R64 and R65 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(g) a group of the formula xe2x80x94CONR66R67, wherein R66 and R67 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R66 and R67 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(h) a group of the formula xe2x80x94OR68, wherein R68 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(i) a group of the formula xe2x80x94SR69, wherein R69 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(j) cyano,
(k) or, an amidino group of the formula 
xe2x80x83wherein R70, R71 and R72 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R70, R71 and R72 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring;
with the proviso that R1 and R2 are in the trans configuration;
and pharmaceutically acceptable salts thereof.
Even more preferred are compounds of the formula I, wherein:
m is 0 or 1,
n is 0 or 1, and
m+n is equal to either 1 or 2;
Y is an oxygen atom;
Z is an oxygen atom;
R1 is:
(A) a hydrogen atom, or
(B) methyl;
R2 is:
xe2x80x83phenyl,
xe2x80x83wherein one or more of the hydrogen atoms of said phenyl group may be optionally and independently replaced with:
(i) R14, which is aryl selected from the class consisting of phenyl, 3-pyridyl, or 5-pyrimidinyl,
 wherein one or more of the hydrogen atoms of said R14 aryl group may be optionally and independently replaced with:
(a) methyl,
(b) cyano,
(c) nitro, or
(d) halogen,
(ii) cyano,
(iii) nitro, or
(iv) halogen;
R3 is a hydrogen atom;
R4 is Cl;
X is xe2x95x90CHxe2x80x94;
R6 is Cl;
R7, R8 and R9 are each, independently:
(A) a hydrogen atom,
(B) an oxo group, or
(C) R34 or xe2x80x94OR34,
xe2x80x83wherein R34 is defined as:
(i) a hydrogen atom,
(ii) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with:
(a) oxo,
(b) phenyl,
xe2x80x83wherein one or more hydrogen atoms of said phenyl group may be optionally and independently replaced with:
(1) alkyl of 1 to 3 carbon atoms,
(2) xe2x80x94COOH,
(3) a group of the formula xe2x80x94NR36R37, wherein R36 and R37 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R36 and R37 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(4) a group of the formula xe2x80x94OR40, wherein R40 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or
(5) an amidino group of the formula 
xe2x80x83wherein R42, R43 and R44 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of R42, R43 and R44 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(c) a group of the formula xe2x80x94OR48, wherein R48 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(d) a group of the formula xe2x80x94NR50R51, wherein R50 and R51 are each, independently,
(1) a hydrogen atom,
(2) alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, or
(3) a group of the formula xe2x80x94(CH2)tCOOH, wherein t is O, 1 or 2,
xe2x80x83or wherein R50 and R51 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, or
(iii) a branched or unbranched carboxylic acid group of 2 to 6 carbon atoms,
(iv) an amidino group of the formula 
xe2x80x83wherein r is 2, 3, 4, 5 or 6, and R56, R57 and R58 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R56, R57 and R58 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(v) phenyl,
xe2x80x83wherein one or more hydrogen atoms of said phenyl group may be optionally and independently replaced with:
(a) alkyl of 1 to 3 carbon atoms,
(b) xe2x80x94COOH,
(c) a group of the formula xe2x80x94NR64R65, wherein R64 and R65 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R64 and R65 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(d) a group of the formula xe2x80x94OR68, wherein R68 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(e) or, an amidino group of the formula 
xe2x80x83wherein R70, R71 and R72 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R70, R71 and R72 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring;
with the proviso that R1 and R2 are in the trans configuration;
and pharmaceutically acceptable salts thereof.
Further preferred are compounds of the formula I, wherein:
m is 0;
n is 1;
Y is an oxygen atom;
Z is an oxygen atom;
R1 is;
(A) a hydrogen atom, or
(B) methyl;
R2 is:
xe2x80x83phenyl,
xe2x80x83wherein one or more of the hydrogen atoms of said phenyl group may be optionally and independently replaced with:
(i) R14, which is aryl selected from the class consisting of phenyl, 3-pyridyl, or 5-pyrimidinyl,
(ii) cyano,
(iii) nitro, or
(iv) halogen;
R3 is a hydrogen atom;
R4 is Cl;
X is xe2x95x90CHxe2x80x94;
R6 is Cl;
R7, R8 and R9 are each, independently:
(A) a hydrogen atom,
(B) an oxo group, or
(C) R34 or OR34,
xe2x80x83wherein R34 is defined as:
(i) a hydrogen atom,
(ii) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- or polysubstituted with a group of the formula xe2x80x94OR48, wherein R48 is a hydrogen atom, or an alkyl of 1 to 7 carbon atoms;
with the proviso that R1 and R2 are in the trans configuration;
and pharmaceutically acceptable salts thereof.
Especially preferred compounds include:
2-(3,5-Dichlorophenyl)-7-(R*)-phenyl-7a-(R*)-tetrahydropyrrolo[1,2-c]imidazole-1,3-dione;
2-(3,5-Dichlorophenyl)-7a-(R*)-methyl-7-(R*)-phenyl-tetrahydropyrrolo[1,2-c]imidazole-1,3-dione;
7-(R*)-(4-Bromophenyl)-2-(3,5-dichlorophenyl)-7a-(R*)-tetrahydropyrrolo[1,2-c]imidazole-1,3-dione;
2-(3,5-dichlorophenyl)-8a-(R*)-methyl-8-(R*)-phenyl-tetrahydroimidazo[1,5-b]pyridine-1,3-dione;
2-(3,5-dichlorophenyl)-8a-(S*)-methoxy-8-(R*)-phenyl-tetrahydroimidazo[1,5-b]pyridine-1,3-dione;
7-(R*)-(4-Bromophenyl)-2-(3,5-dichlorophenyl)-7a-(R*)-methyl-tetrahydropyrrolo[1,2-c]imidazole-1,3-dione,
2-(3,5-dichlorophenyl)-7-(R*)-[4-(3-pyridyl)phenyl]-7a-(R*)methyl-tetrahydropyrrolo[1,2-c]imidazole-1,3-dione;
7-(R*)-(4-Bromophenyl)-2-(3,5-dichlorophenyl)-6-(S*)-hydroxy-7a-(R*)-tetrahydropyrrolo[1,2-c]imidazole-1,3-dione;
7-(R*)-(4-Bromophenyl)-2-(3,5-dichlorophenyl)-7a-(R*)-allyl-tetrahydropyrrolo[1,2-c]imidazole-1,3-dione; and,
7-(R*)-(4-Bromophenyl)-2-(3,5-dichlorophenyl)-5-(S*)-hydroxy-7a-(R*)-methyl-tetrahydropyrrolo[1,2-c]imidazole-1,3-dione;
and pharmaceutically acceptable salts thereof.
In the names of the above-mentioned preferred compounds, the * denotes relative stereochemistry, not absolute stereochemistry.
It will be appreciated that the compounds of formula I have at least one chiral center. Ultimately preferred are those compounds of formula I with the absolute stereochemistry depicted below in formula Ia. 
The starting amino acids and their derivatives necessary for the synthesis of the compounds of the examples are either commercially available or are produced by obvious modifications of known literature. In particular, the method of Chung et al., J. Org. Chem. 1990, 55, 270-275 teaches the synthesis and resolution of 3-substituted proline derivatives. When not obvious, the synthesis of the starting material is described. General methods for the synthesis of compounds of the invention are described below and illustrated in Scheme I. 
An appropriate amino acid is dissolved in aqueous base (such as, for example, NaOH, KOH, Na2CO3, NaHCO3, K2CO3 or KHCO3) and warmed to between about 20 and 90xc2x0 C. An appropriate isocyanate is added to this mixture and the resulting solution was stirred until the reaction essentially reaches completion. Upon cooling, the mixture is acidified and the resulting ureidoacetic acid is isolated by filtration or by extraction into organic solvent. Removal of solvent produces an intermediate which is cyclized by heating in the presence of a catalytic amount of acid (such as, for example, sulfuric acid, methanesulfonic acid, benzenesulfonic acid or hydrochloric acid) in an organic or aqueous solvent, to produce the desired hydantoin. Workup consists of collection of the desired product by filtration and purification by, for example, silica gel chromatography or recrystallization.
An appropriate amino acid is dissolved in aqueous base (such as, for example, NaOH, KOH, Na2CO3, NaHCO3, K2CO3 or KHCO3) and warmed to between about 20 and 90xc2x0 C. An appropriate isocyanate is added to this mixture and the resulting solution is stirred until the reaction essentially reaches completion. Upon cooling, the mixture is acidified and the resulting ureidoacetic acid is isolated by filtration or extraction into organic solvent. Removal of solvent produces the intermediate ureidoacetic acid which is then cyclized to the desired product in organic solvent (such as, for example, DMF, NMP, or THF) using any of a number of dehydrating agents (such as, for example, dicyclohexylcarbodiimide (DCC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (EDC)) in the presence of an activating agent (such as 1-hydroxybenzotriazole hydrate (HOBT)) and a non-nucleophilic base (such as, for example, triethylamine or N,N-diisopropylethylamine). Work up consists of extraction into an organic solvent followed by purification via, for example, silica gel chromatography or recrystallization.
An appropriate amino ester or hydroxy ester and an appropriate isocyanate are dissolved in an organic solvent (such as, for example, DMF, THF or DMSO) in the presence of a base (such as, for example, NaOH, KOH, Na2CO3, NaHCO3, K2CO3 or KHCO3) and warmed to between about room temperature and 60xc2x0 C. After approximately 1 h, the temperature of the reaction mixture is raised to between about 50 and 100xc2x0 C. until the reaction appears complete. The solution is then cooled and diluted with an organic solvent (such as, for example, EtOAc or CH2Cl2). The organic phage is washed sequentially with dilute aqueous acid (e.g. 1 NHCl) and water, dried (e.g. over MgSO4)and concentrated. The desired product is purified, for example by silica gel chromatography or by recrystallization. (Alternatively the ureidoacetic ester can be cyclized to the product by heating to between about 50 and 100xc2x0 C. in the presence of an acid such as, for example, aqueous HCl until the reaction appears complete).